Contrast agents are widely used to improve x-ray or magnetic imaging of soft tissues. Compared to tissue, the heavy elements in diagnostic contrast media have greater capacity to absorb low-energy x-rays. This advantage is described as a higher x-ray “cross section”, and is measured by the substance's attenuation coefficient. The preferential blocking of x-rays by a heavy element allows an area to stand out against the background for better imaging, yet also results in more radiation dose delivered to the region nearby. This enhancement of absorbed dose from the contrast media used in radiographic imaging has been viewed as potentially dangerous. Concerns about increased cell damage caused by high radiation doses coming off contrast agents led to the idea that the potentially harmful effects could be exploited to improve radiotherapy
Contrast-enhanced radiotherapy (CERT) utilizes previously neglected effects of x-rays absorbed by radiographic contrast agents (U.S. Pat Nos. 6,125,295 and 6,366,801 and U.S. application Ser. No. 11/671,222). Resulting secondary ionizing radiation transfers significant energy and damages a limited volume. After concentrating contrast in a lesion, a lethal radiation dose can be delivered quickly to a lesion with minimal toxicity to nearby tissue. Our previous clinical development of CERT demonstrated the technique could safely create tumor debris in situ. A phase I trial of the technique in advanced cancer patients demonstrated the ability to precisely deliver high doses of x-rays to tumors with no toxicity and good palliation (Weil et al., “Phase I Study of Contrast-Enhanced Radiotherapy with GMCSF for Advanced Cancers,” Submitted, 2007).
The most important interactions between 120-150 kVp x-rays and a contrast agent are the attenuation (measured as, μen, mass attenuation coefficient) and energy transfer (measured as, μen/p, mass energy-absorption coefficient) as a result of collisions with the electrons in a high Z element, such as iodine. Iodine is commonly used for imaging since it is the high Z element in commercially available CT contrast media
The image reconstruction algorithm of a CT scanner employs numbers, Hounsfield units (HU), which are calculated as the beam spectrum is attenuated by the tissue in the patient,HU=1000(μtissue−μwater)/μwater  (Eqn. 1);
where, μtissue and μwater, are the linear attenuation coefficients for tissue and water, respectively. Thus, the CT numbers (HU) have a linear relationship with the x-ray attenuation coefficients, and a Hounsfield Unit represents a change of 0.1% in the attenuation coefficient of water.
Marketed CT software readily acquires HU of injected pixels directly from the image. From the measured HU, the known mass attenuation coefficients from the National Institute of Standards and Technology for a given beam energy can be used to derive the concentration of iodine. In the above equation, μtissue is replaced by,μiodine×[iodine concentration].
On the other hand, the accompanying increase in energy transfer can enhance the dose delivered to a lesion by more than an order of magnitude. The dose enhancement factor (DEF) can be calculated for iodine versus water at a given energy as:
                              DEF          =                                                                                          (                                          μ                                              cn                        /                        ρ                                                              )                                    1                                *                                  f                  1                                            +                              [                                                                            (                                              μ                                                  cn                          /                          ρ                                                                    )                                                              H                      ⁢                                                                                          ⁢                      2                      ⁢                      O                                                        *                                      (                                          1                      -                                              f                        1                                                              )                                                  ]                                                                    (                                  μ                                      cn                    /                    ρ                                                  )                                            H                ⁢                                                                  ⁢                2                ⁢                O                                                    ;                            (                  Eqn          .                                          ⁢          2                )            
where μen/p is the mass energy-absorption coefficient of iodine or water (at the spectral energy), and f1 is the fraction by weight of iodine in the lesion.
The DEF can be as high as 37:1 with commercially available iodinated-CT contrast media, which was sufficient to destroy most tumors in our study. Moreover, the delineation between the high dose in the contrast-painted tumor to the low dose in the tissue takes place in under 50 μm(<10−4 m). Comparable fall-off for all other therapeutic radiation techniques, e.g., megavoltage beams, seeds, particles, is on the order of centimeters (10−2 m).
An infused lesion is imaged and the concentration of high Z material in the target is determined. If the imaging is done with a CT scanner the CT numbers (Hounsfield Units) can be used to calculate the dose enhancement factor for CERT. Likewise, if a different type of digital detector is employed the dose enhancement factor can be derived from the attenuation coefficients measured with multiple beams. If, after calculating the dose enhancement factor for CERT, the potential enhancement is too low, the contrast infusion is repeated until there is sufficient high Z material in the target to produce adequate dose enhancement. Following delivery of radiation agents and confirmation of a minimal contrast concentration; the lesion is treated with radiation. The radiation is best delivered with external radiation beams from multiple directions. It is extremely difficult to deliver radiotherapy beams from multiple directions with existing kilovoltage technology.
Another critical component of this invention is quantification and dosimetry of the delivered dose of radiation. The penetration of the radiation through tissue will decrease the flux and also change the spectrum by hardening the beam, i.e., the average beam energy increases as lower energy photons are attenuated and higher energy photons relatively predominate. These parameters are influenced by the residence time of the radiation agent in the tumor and are dependent upon the kinetics of diffusion out of the target site. In clinical practice these variables are accounted for and the DEF is calculated with planning software.
This invention does not employ radiopharmaceuticals. The high doses to the organs when using radioactive targeting moieties limit the use of the technology. The utility of the radiation treatment agents with dual-use collimation of kilovoltage radiation described herein, especially absent attached radioactive isotopes, for enhancing the effect of radiation therapy has not been taught elsewhere.
The types of tumors that can be treated by this invention include primary and metastatic bone and soft tissue tumors. When the location of these tumors is known, one modality of treatment is to administer the radiation agent, then concentrate the radiation to the area of the tumor, thus increasing the ratio of absorbed radiation dose in the target versus normal tissue. In other cases, where many tumors are in need of treatment, or where there is disseminated disease, it is possible to administer the radiation agent then give relatively low radiation to the whole body. This way of treating the patient may treat micro-metastatic sites, or small tumors, before they grow into bigger and less treatable tumors.
Contrast agents and tumor targeting techniques at present do not achieve adequate tumor concentration of heavy atoms for CERT except with direct intratumoral injection of contrast (U.S. Pat. Nos. 6,125,295 and 6,366,801 and Weil et al., “Phase I Study of Contrast-Enhanced Radiotherapy with GMCSF for Advanced Cancers,” Submitted, 2007). In the example from Hainfeld et al (U.S. Pat. Nos. 6,645,464 and 6,955,639) employing intravenous delivery of gold nanoparticles into experimental mouse tumors; they measured gold uptake in the tumor at 0.23% weight/volume. However, for practical implementation of CERT, it is necessary to obtain ˜2.5-30% weight/volume of a heavy element in a tumor. Therefore, as reported in this study with gold nanoparticles, the dose enhancement would be 10-100 times less than required for clinical efficacy.
The prospects of safely using kilovoltage beams even for tumors at depth are improved with a significant DEF. Rather than overdosing the skin in an effort to increase the radiation dose to a deep lesion, the DEF may enable treatment with lethal dosing of the tumor and relatively low dose to the skin. However, as a result of significant tissue absorption of kilovoltage x-rays, tumors deeper than 5 cm require multiple beams in order to safely deliver an adequate radiation dose.
Others have employed devices to use a single machine for imaging and therapy. Norman et al have described treatments employing a kilovoltage computerized tomography scanner with collimation altered to produce a pencil beam, a small round or rectangular beam (U.S. Pat. No. 5,008,907; Iwamoto et al., “The CT scanner as a therapy machine,” Radiother. Oncol. 19:337, 1990, Elsevier; Solberg et al., “Calculation of radiation dose enhancement factors for dose enhancement therapy of brain tumours,” Phys. Med. Biol. 37:439, 1992, Inst, Phys. Pub.; Iwamoto et al., “Diagnosis and treatment of spontaneous canine brain tumors with a CT scanner,” Radiother. Oncol. 26:76, 1993, Elsevier; Norman et al., “X-Ray phototherapy for canine brain masses,” Radiat. Oncol. Investig. 5:8, 1997, John Wiley and Sons.; Mesa et al., “Dose distributions using kilovoltage x-rays and dose enhancement from iodine contrast agents,” Phys. Med. Biol. 44:1955, 1999, Inst. Phys. Pub.; Rose et al., “First radiotherapy of human metastatic brain tumors delivered by a computerized tomography scanner (CTRx),” Int. J. Radiat. Oncol. Biol. Phys. 45:1127, 1999, Elsevier). These treatments were done with fractionated radiotherapy. The use of megavoltage computerized tomography capable of imaging and treatment has also been developed (U.S. Pat. No. 6,618,467).
The therapeutic profile of contrast-enhanced radiotherapy can be of benefit since tumor control rates are better with increased radiation doses. To satisfactorily enhance the kilovoltage radiation dose absorbed by a solid tumor in the presence of a high Z element, it is necessary to be able to safely deliver adequate radiation to all locations in the body. Improved efficacy and/or control of such delivery are desired.